Lack of blood flow (ischemia) to the eye may result in death of the tissues in the optic nerve and retina/choroid. In the case of central retinal artery occlusion (CRAO), there is a particle (embolus) in the major blood vessel giving oxygen and nutrients to the retina. In the case of anterior ischemic optic neuropathy (AION), there may be an occlusion of the blood vessel(s) entering the eye in the anterior optic nerve. With optic neuritis (ON) involving the anterior optic nerve, there is an inflammation of the optic nerve due to disease in the myelin sheath, the covering of the nerve fibers that exit the eye. After a period of time (minutes to hours to days), death of the tissue may occur causing irreversible damage.
Pathology to tissues of the eye may occur due to blunt injuries, such as a blow to the eye/orbit, resulting in hemorrhage within or around the eye and associated swelling of eye tissue. Unfortunately, it is often difficult to control injury to the eye using conventional opthalmological means including medical and surgical intervention.
Various other diseases of the eye and the orbit may result in swelling of tissue with consequent loss of function. Inflammation of orbital tissue is usually managed with systemic medical therapy or even surgical decompression. Other types of inflammation of the tissues within the eye include posterior uveitis, choroiditis, retinitis, vitritis, scleritis, thyroid-related eye disease, phacoanaphylaxis, anterior uveitis, and sympathetic ophthalmia. Secondary glaucoma may result from inflammation involving the anterior segment of the eye.
Infections of the eye may involve the cornea, the sclera, the vitreous, the retina/choroid, the ciliary body, the lens, and the anterior chamber. They are usually treated with systemic antibiotics, occasionally systemic steroids, and topical drops of antibiotics, and intraocular antibiotic injections.
Current treatment for swelling or inflammation of the eye and orbit is not always satisfactory. In the severely injured eye or orbit, medical therapy to control swelling is usually applied systemically resulting in high levels of medication in the rest of the body with very low concentrations reaching the eye or orbit. Surgical intervention to decompress the eye and/or orbit requires major intervention through opening the bony walls of the orbit or skull to expose the area and prevent compression against the fixed volume of the bony walls. In the case of severe swelling of the sheath around the optic nerve, surgical decompression of the sheath has been attempted in severe cases of papilledema, anterior ischemic optic neuropathy, and severe trauma. The results have variable reports of success and failure of the procedures.
Age-related macular degeneration (AMD) is by far the most common cause of severe central vision loss in the Western World and has a profound effect on older adult daily activities. Age-related macular degeneration is an age and light related stress to macular cells, which break down and scar down. The dry form accounts for roughly eighty to ninety percent of all cases of AMD. The wet form of AMD or neovascular AMD, the other ten to twenty percent of all cases of AMD, involves abnormal blood vessel formation under the macula leading to subretinal fluid, subretinal hemorrhage and severe macular scarring. Wet age-related macular degeneration affects roughly 1.2 to 2 million people in the United States alone. Currently, around 8.2% of Americans over eighty years in age have wet AMD. Macular degeneration is more prevalent among white women, with more than 15% older than 80 years having wet AMD and/or geographic atrophy. Aging baby boomers will lead to higher prevalence of wet AMD in the next decades.
Most untreated eyes quickly deteriorate to less than 20/200 vision and eventually only counting-finger vision. Steroids and anti-angiogenic factors such as anti-VEGF (anti-vascular endothelial growth factor) have been used to suppress neovascularization. Anti-VEGF treatments currently available include ranibizumab (Lucentis) and pegaptanib sodium (Macugen). Lucentis is an antibody fragment that binds to VEGF and inhibits its activity. Macugen, an anti-VEGF aptamer that binds to one particular form of VEGF in the eye, neutralizes its activity. Lucentis has been especially promising. For example, Lucentis improves vision in 33% of patients with minimally classic or ocult neovascularization at two years into treatment. Other monoclonal antibodies, antivectus techniques and other biologic factors will be available in the near future. The current method of anti-angiogenic administration is intra-vitreal injection, which is invasive and puts the eye at risk for endophthalmitis, detached retina, and scarring. A better delivery technique is needed.
Hypothermia has proved encouraging in the recent literature for the purpose of decreasing oxygen consumption and for decreasing swelling of the brain and other central nervous system (CNS) tissue. Since the eye is part of the CNS, it seems logical that hypothermia of the eye may decrease swelling of the eye and optic nerve in the same way as hypothermia of the brain prevents brain swelling. Unfortunately, cooling of the entire body to cool the brain does have inherent dangers, and similarly cooling of the eye by cooling the body may also have deleterious effects. The heart responds to hypothermia with arrhythmias, and the blood clotting mechanisms may be severely impaired resulting in hemorrhage. Moreover, cooling the body only results in a few degrees of cooling of the CNS. In the case of the eye, attempts have been made to cool the vitreous of the eye during retinal and vitreous surgery by surgically entering the eye and cooling it from within. A recent animal study on viability of CNS tissue of the eye after hypothermia demonstrated similar preservation of function.
Cooling the eye, eyelids, periorbita and orbits from the outside surface without surgery can decrease inflammation, minimize apoptosis and ischemic injury without the usual complications of invasive modalities. Thermal regulation of the eye when combined with other treatment modalities may further improve treatment outcome. For example, hypothermia in combination with ionotophoresis, can offer unique treatment results not previously attainable. Iontophoresis through the thin equatorial sclera of the eye can potentially improve intraocular delivery of medications.
Iontophoresis is a non-invasive technique for infusing charged molecules, medications, and other biochemicals into biological tissues via a weak electric current. A weak electrical charge, when applied to a permeable iontophoretic medicament chamber containing similarly charged molecules in solvent, gel vehicle, gel sponges, cross-linked hydrogels or other matrixes, will repel these charged particles into the neighboring tissue. This movement is controlled by the Lorentz force within this weak electric field created around this weak electric current.
Iontophoresis is currently not a commercially available therapeutic modality for the eye. There are now many drugs available to the eye physician who would prefer to deliver them safely to the entire eye, the posterior segment of the eye, the posterior orbit and optic nerve. Topical eye drops deliver medications to the ocular surface including the cornea and conjunctiva; corneal absorption is very poor for some medications due to the lipophilic corneal barrier. Systemic injection and oral administration of medications, which can be associated with many potential systemic side effects and adverse reactions, may yield very low drug concentration to the back of the eye, the vitreous cavity, the posterior orbit and the optic nerve. Subconjunctival and subtenon's injections are usually associated with a significant amount of medicament carried away by the rich conjunctival and Tenon's vasculature. Intraocular injections, such as vitreous injections and intra-cameral injections, carry risks of intraocular infection, bleeding, retinal complications and other iatrogenic adverse effects. Orbital injections, including peri-bulbar and retro-bulbar injections, are still invasive and associated with potential complications including retro-bulbar or peri-bulbar hemorrhage and infection. It may be difficult to control a constant administration of the medication over a predictable desired duration. An example is the long term elevation of intraocular pressure following a subconjunctival or intra-vitreal injection of depo-steroid.
Prior attempts to deliver medications via transcorneal iontophoresis were associated with very low vitreous drug concentrations and considerable systemic drug concentrations. The pitfalls were partially due to the failure to recognize that it would be best to avoid the lipophyllic cornea which is poorly peameable to some medicaments. U.S. Pat. No. 6,319,240 by Beck continued to teach the placement of the medicament chamber of the ocular iontophoresis device on the cornea. This patent recognized the permeability of the sclera but, rather than suggesting that the permeable sclerae be used for entry and delivery of medications, the embodiments described in this patent primarily involved corneal delivery techniques. They observed that medicaments and electric currents were diverted along the paths of least resistance on the ocular surface and away from the eye to other more vascularized peri-orbital soft tissues. Scleral barriers are described in the patent to keep the medications from escaping to the surrounding eyelids and peri-orbital tissues. This same patent only briefly described and illustrated a small iontophoretic patch to be placed on the inferior conjunctiva and sclera.
In U.S. Pat. No. 6,154,671, Perel and Behar described ocular iontophoretic devices containing various annular medicament reservoirs basically at the limbus and limbal scleral and with little contact with more posterior sclera. Return electrode placement in relation to the active electrode in one embodiment, the menicus flat device, does not favor the driving of medications into the eye because the resultant current travelling between these two electrodes is significantly above the scleral surface. In other embodiments, the return electrodes complete the circuit by touching the eyelids, again diverting current and iontophoresis to the eyelids and away from the eye. Barriers to prevent unwanted diffusion of medications are not well described.
Scleral inserts in an annular shape have been described by Roy in US Patent 2006/0142706. These polymer scleral inserts have medicament reservoirs to release medicament through the microporous walls; these inserts are not intergrated with an iontophoresis device. This patent mentions that an iontophoretic device known in the art can be placed in the vicinity of the scleral inserts. This patent further mentions that the inserts can contain electrodes but doesn't described how they could be attached to a doses controller of an iontophoretic device nor how barriers can be constructed to minimize medicament loss.
The sclera and conjunctivae, in contrast to the corneal barrier, are known to be quite permeable to even large biological molecules. A more effective transscleral drug delivery route than what has been previously described is desirable. Maximizing the scleral contact area should be utilized. Iontophoresis can enhance the delivery of charged medicaments across the broader sclera. Hypothermia can potentially enhance medicament delivery by vasoconstriction to prevent unwanted diffusion of medicaments systemically.
With the new technologies now available, it is time for a new approach to controlling the temperature of the CNS and the eye and orbit by doing local cooling from outside surface of the eye without entering the eye surgically. Furthermore, hypothermia intergrated with iontophoresis can offer improved medicament delivery to the eye, optic nerve and orbits. By administering medications via iontophoresis, microneedles or other means to the eye/orbit directly in a continuous fashion coupled with hypothermia, there may be a new approach to treating eye disease. Better designs of electrodes and better placement of medicament reservoirs for ocular iontophoresis are described in this patent.